Investigational Drug in Combination With Two Chemotherapy Drugs in Women With Locally Recurrent or Metastatic Breast Cancer

Endocrine therapy and chemotherapy (using either sequential single agents or combination regimens) remain the principal treatments for women with metastatic breast cancer. A wide variety of classes of chemotherapeutic agents have demonstrated anti-tumor activity as single agents or in combination regimens. Cytotoxic chemotherapeutic agents have been the mainstay of cancer therapies for many years and have improved survival in many disease settings. Median survivals remain approximately two years for women with metastatic breast cancer, and less than 3% of patients experience long-term survival after initiation of treatment. The development of new treatment strategies is therefore essential to improve outcome for patients with metastatic breast cancer.

One of the most promising pathways for the development of new anti-neoplastic agents is targeting tumor vascular endothelium. There is significant preclinical and clinical evidence indicating that tumor neoangiogenesis is critical in pathogenesis and progression of solid tumors, including breast cancer. Of the numerous known growth factors that have been implicated in tumor angiogenesis, vascular endothelial growth factor (VEGF) is one of the important molecules regulating new blood vessel formations and subsequent invasion and metastases. As a result, agents that inhibit VEGF are of substantial interest for the treatment of advanced diseases. More thorough elucidation of mechanisms behind intrinsic and acquired resistance therefore is imperative disease and to identify patients most likely to benefit from treatment options.

Motesanib has been shown in preclinical pharmacology and PK studies to be a potent, orally bioavailable multi-kinase inhibitor with anti-angiogenic and anti-tumor activity achieved by selectively targeting all known VEGF, PDGF and Kit receptors. It has an acceptable safety profile in both non-clinical and clinical studies, and a PK profile that appears suitable for daily oral dosing in humans.

The investigational product motesanib (Amgen) is a small molecule tyrosine kinase inhibitor with high efficacy against VEGFR and c-Kit kinases. C-kit has been detected in 12% of breast cancers, correlating with basal or triple-negative breast cancer. In addition, efficacy of the drug has been noted to PDGFRα, which is expressed in approximately 40% of breast cancers and is associated with aggressive disease, metastatic invasion and poor prognosis. Importantly, in more than half (56%) of these cases, the carcinoma cells bearing the receptors expressed the PDGF-A ligand, suggesting an autocrine loop and a cancer cell-autonomous process. Cancer cell-autonomous pathways are especially attractive as drug targets against metastatic breast cancer because they are expected to continue to be functional at metastatic sites, since they do not depend on stromal factors.